DE69529142T2 - TETRAHYDROPYRIDINE (OR 4-HYDROXYPIPERIDINE) ALKYLAZOLES WITH SIGMA AND / OR 5HT 1A RECEPTOR ACTIVITY - Google Patents

Abstract

The present invention relates to the compounds of general formulaused as medicaments possessing therapeutic activity for the treatment of anxiety, psychosis, epilepsy, convulsion, motoricity problems, amnesia, cerebrovascular diseases or senile dementia.

Description

The present invention relates to novel alkylazole-linked 4-aryltetrahydropyridines and 4-arylpiperidinols of the general formula (I)

and their physiologically acceptable salts, processes for their preparation, their use as medicines and the pharmaceutical compositions containing them.

The compounds which are the subject of the invention can also be used in the pharmaceutical industry as intermediates and for the manufacture of medicaments.

These compounds have a strong affinity for the sigma and/or 5HT1A receptors and are therefore potentially useful in the treatment of certain mental and neurological disorders in humans and other mammals.

There are facts that implicate the sigma receptors in the treatment of psychoses. Numerous atypical antipsychotics, such as rimcazole (Schwarcz, G. et al., Drug Dev. Res., 1985, 5, 387), remoxipride (Wadworth, A. N. et al., Drugs 1990, 40, 863), thiospirone (Jain, A. K. et al. Int. Clin. Psychopharmacol. 1987, 2, 129) show a significant affinity to the sigma receptors.

On the other hand, studies of the biology and function of sigma receptors indicate that sigma receptor ligands may be effective in the treatment of certain motor disorders, in particular Huntington's disease, dystonia and Tourette's syndrome. The presence of sigma receptors in the substantia nigra allows their use in the treatment of Parkinson's disease (Walker, J. M. et al. Pharmacological Reviews, 1990, 42, 355).

Certain ligands of the sigma receptors are related to the modulation of effects produced by the NMDA receptor mediation and act as anti-ischemic agents in in vivo tests (Rao, T. S. et al., Molecular Pharmacology, 1990, 37, 978) with the possibility of use as neuroprotectors and in the treatment of epilepsy and convulsions (Kaiser C. Neurotransmissions VII, 1991).

Ligands of the sigma receptors have been reported to exhibit antiamnesic effects in animal models (Early et al., Brain Research 1991, 546, 281).

The sigma ligands act on acetylcholine levels in animal models (Matsuno et al., Brain Research 1992, 575, 315) and can therefore be used in the treatment of senile dementia, e.g. of the Alzheimer type.

The ligands of the 5-HT1A receptors, especially the agonists or partial agonists of 5-HT1A, show proven anxiolytic and antidepressant effects (Glitz, DA Drugs, 1991, 41,11).

Accordingly, agents having a strong affinity for sigma and/or 5-HT1A receptors may be used in one or more of the indicated treatments.

Examples of 4-aryl-1,2,3,6-tetrahydropyridines and 4-aryl-4-hydroxypiperidines can be found in the literature; however, there is no description of compounds in which these substructures are linked to the nitrogen of an azole nucleus by means of an unsubstituted alkyl chain:

Davis L. Temple et al., U.S. Patent 4,320,131; March 16, 1982

Richard A. Glennon et al., J. Med. Chem., 1991, 34, 3360-65

Jean-Luc Malleron et al., J. Med. Chem. 1991, 34, 8, 2477-83

Henning Böttcher et al., J. Med. Chem. 1992, 35, 4020-28

Zhuihua Sui et al., Synthesis, 1993, 803-8

David I. Schuster et al., J. Med. Chem. 1993, 36, 3923-28

David J. Wustrow et al., BioMed. Chem. Lett., 1993, 3, 277-80

Shimazaki Norihiko et al., Kan. Pat. Note, CA 2053475 AA.

The inventors have previously described a series of N-alkylazoles linked to the nitrogen of various heterocycles which are useful as non-benzodiazepine agents for the treatment of anxiety (European patents nos. EP 382637, EP 497659 and EP 502786) and for the treatment of other behavioural disorders (European patents EP 429360 and EP 497658). In the patents cited, compounds of general formula (I) are described in which A in each case represents a nitrogen atom and is accordingly a piperazine nucleus. In the present invention, the piperazine nucleus is replaced by piperidine or tetrahydropyridine.

Document US 4,675,403 also describes 4-hydroxypiperidinealkylimidazolidine compounds which have antipsychotic and anxiolytic activity. These compounds comprise in particular a saturated nitrogen heterocycle substituted by two carbonyl groups.

The subject of patent application WO 94/13659 are imidazolidinones, imidazolones, benzimidazolines and piperazines which comprise carbonyl functions and have an affinity for the 5-HT1A receptors.

Derivatives of tetrahydropyridine which have an affinity for γ-receptors are described in the patent application EP 445 701. These derivatives are substituted by a saturated nitrogen heterocycle, an amine or an amide. They can be used as antipsychotic agents.

Hudkins et al. describe in Biorganic and medicinal chemistry letters, volume 4, no. 18, pages 2185-2188, 1994, ligands of γ-receptors whose basic structure corresponds to 5,5-diphenylhydantoins substituted by 4-phenylpiperidinyl or 4-phenylpiperazinyl.

The compounds which are the subject of the invention correspond to the general formula (I)

in the

R₁, R₂ and R₃, identical or different, each represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a perhalogen radical, an aryl or substituted aryl radical or an alkoxy radical; moreover, two adjacent radicals can form an aromatic or saturated cycle;

A represents a carbon atom and the dashed line represents an additional bond or A represents a carbon atom bonded to a hydroxyl group and the dashed line represents the absence of an additional bond;

n has values from 2 to 6, preferably 4;

Z₁ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₄;

Z₂ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₅;

Z₄ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₇;

R₄, R₅, R₆ and R₇, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a carboxyl radical, a carboxamide radical, an alkylcarboxylate radical, an aryl or substituted aryl radical, a hydroxyl radical, an alkoxy radical, or two adjacent radicals can be part of another cycle, aromatic or not.

The invention also relates to the physiologically acceptable salts of the compounds of general formula (I), in particular the salts of hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic acid and of alkyl, cycloalkyl or arylsulphonic acids.

The rest

represents an azole, with the exception of tetrazoles in which 21, 4 and 4 simultaneously represent a nitrogen atom.

If R₄, R₅, R₆ and R₇ are not part of another aromatic or non-aromatic cycle is preferably an azole in which a single one of Z₁, Z₂ or Z₄ represents a nitrogen atom, in particular a pyrazole (Z₁ or Z₄ = N) or an imidazole (Z₂ = N).

When R4, R5, R6 or R7 form part of another aromatic or non-aromatic cycle, the "azole" moiety of the above radical remains essential, that is to say, it does not include radicals such as β or γ-carbolines, pyrroloazepines and radicals comprising carbonyl functions such as pyrazolones, imidazolones, benzimidazolones and, in general, heterocycles comprising a carbonyl function.

Preferably, when R4, R5, R6 or R7 form part of another aromatic or non-aromatic cycle, the above radical preferably represents a bicyclic radical, in particular indole, indazole, benzimidazole or benzotriazole.

Linear or branched alkyl is preferably understood to mean a (C₁-C₆)-lower alkyl, in particular methyl, ethyl or propyl, this definition also applying to alkyl radicals of alkoxy radicals or alkyl carboxylates.

Aryl or substituted aryl is preferably understood to mean phenyl optionally substituted by one or more radicals selected from halogens and linear or branched alkyls.

Halogen means fluorine, chlorine or bromine, preferably chlorine.

Finally, perhaloalkyl is understood to mean a linear or branched alkyl radical in which all hydrogen atoms are replaced by halogens. It is preferably a perfluoroalkyl radical, in particular trifluoromethyl.

The new derivatives of the general formula (I) can be prepared according to the following procedures.

Method A:

By reacting a spirane derivative of the general formula (II):

in the

R₁, R₂, R₃ and A have the meaning given above, m can assume values from 0 to 4 and X represents a leaving group such as chlorine, bromine, mesyloxy or tosyloxy, with a nitrogen heterocycle of the general formula (III)

in the

Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is effected in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene, or an aliphatic hydrocarbon such as hexane, or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The reaction time varies between 1 and 24 hours.

Method B:

By a simultaneous "one-pot" reaction between a derivative of the general formula (IV), an alkylating agent of the general formula (V) and a nitrogen heterocycle of the general formula (III)

wherein

R₁, R₂, R₃, A, X, n, Z₁, Z₂, Z₄ and R₅ have the meaning given above.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene, or an aliphatic hydrocarbon such as hexane, or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The response time varies between 1 and 24 hours.

Procedure C:

The preparation of compounds of general formula (I) can be carried out by reacting amines of general formula (IV)

in the

R₁, R₂, R₃ and A have the meaning given above, with compounds of the general Formula (VI)

in the

X, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above, under alkylation conditions.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene, or an aliphatic hydrocarbon such as hexane, or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The response time varies between 1 and 24 hours.

Procedure D:

The preparation of compounds of general formula (I) can be carried out by reacting a compound of general formula (VII)

in the

R₁, R₂, R₃ n and A have the meaning given above, with a nitrogen heterocycle of the general formula (III)

in the

Z₁, Z₂, Z₄ and R₆ have the meaning given above, under alkylation conditions.

The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene, or an aliphatic hydrocarbon such as hexane, or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The response time varies between 1 and 24 hours.

Procedure E:

By dehydration of compounds of the general formula (I)

in the

R₁, R₂, R₃, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above, A represents a carbon atom linked to a hydroxyl group (C-OH), and the dashed line represents the absence of any additional bond.

The reaction is carried out in acidic medium, such as hydrochloric acid, trifluoroacetic acid, sulfuric acid or phosphoric acid or by treatment with thionyl chloride in benzene.

The reaction temperature varies between ambient temperature and 180ºC.

The response time varies between 1 and 14 hours.

Procedure F:

By addition of organometallic reagents - for example phenyllithium or phenylmagnesium bromide - to compounds of the general formula (VIII)

in the

n, Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is carried out in a solution containing an inert solvent, generally an ether such as dimethoxyethane, tetrahydrofuran or ethyl ether.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The response time varies between 5 minutes and 24 hours.

Procedure G:

By reduction of the carbonyl of the amide group of compounds of the general formula (IX)

in the

R₁, R₂, R₃, A, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above.

The reaction is preferably carried out in an inert organic solvent such as ethyl ether or tetrahydrofuran with reducing agents such as LiAlH₄, AlH₃ or diborane.

The reaction temperature varies between ambient temperature and the reflux temperature of the solvent used.

The response time varies between 5 minutes and 24 hours.

Procedure H:

By reacting a compound of general formula (I) with a non-toxic mineral or organic acid in a suitable solvent which may be, for example, an alcohol such as methanol, ethanol or any of the propanols or butanols, an ester such as ethyl acetate, or a nitrile such as acetonitrile; and using conventional techniques of precipitation, crystallization and so on, the corresponding salt is obtained.

The mineral acid is selected from, among others, hydrochloric, hydrobromic, sulphuric or phosphoric acid; and the organic acid from mono-, di- or tricarboxylic acids, such as acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic acid and the alkyl, cycloalkyl or arylsulphonic acids.

The mono- or di-salts of the acid can be formed, and these salts can be in anhydrous or hydrated form.

The invention is described in more detail by the following examples, which are given simply for illustrative purposes, it being understood that they can in no way limit the specific conditions of the process or the scope of the invention.

PROCEDURE A Example 1. Preparation of 4-chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole.

A mixture of 15.0 g (48 mmol) of 8-hydroxy-8-phenyl-5-azoniaspiro[4,5]decane, 5.4 g (53 mmol) of 4-chloropyrazole and 13.2 g of potassium carbonate in 200 ml of dimethylformamide is refluxed for 20 hours. It is then evaporated to dryness under reduced pressure, redissolved in chloroform and washed repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which is suspended in ethyl ether, which is filtered when cold and washed with ethyl ether. 12.4 g are obtained. (37.1 mmol) 4-Chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole.

The melting point and spectroscopic data for identification of this product are given in Table 1.

PROCEDURE B Example 7. Preparation of 4-chloro 1-[4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl]- 1H-pyrazole.

A mixture of 8.6 g (35 mmol) of 4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidine, 7.68 g of 1,4-dibromobutane and 13.8 g of potassium carbonate in 100 ml of dimethylformamide is heated at reflux for 4 hours. 3.59 g (35 mmol) of 4-chloropyrazole are then added and the mixture is refluxed for 14 hours. Then the mixture is evaporated to dryness under reduced pressure, redissolved in chloroform and washed repeatedly with water. The organic phase is dried with anhydrous sodium nitrate and evaporated under reduced pressure to give a crude product which is purified by chromatography on silica gel. 9.7 g (24.2 mmol) of 4-chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole are obtained.

The spectroscopic data for the identification of this product can be found in Table 1.

PROCEDURE C Example 14a. Preparation of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}indole.

A mixture of 4.8 g (30 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl)indole and 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated for 3 hours at 90°C. It is then evaporated to dryness under reduced pressure, redissolved in chloroform and washed repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which is purified by chromatography on silica gel. 5.7 g (17.3 mmol) of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}indole are obtained.

The spectroscopic data for the identification of this product are given in Table II.

PROCEDURE D Example 21a. Preparation of 4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]propyl}-1H-pyrazole.

A solution of 2.05 g (20 mmol) of 4-chloropyrazole in dimethylformamide is added dropwise to a suspension of 1.0 g of NaH in dimethylformamide. The white suspension is heated at 100°C for 30 minutes. It is cooled and then 4.7 g (20 mmol) of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine, dissolved in dimethylformamide, are added. The mixture is heated at reflux for 2 hours. The mixture is then evaporated to dryness, the residue is extracted with chloroform, washed with water and dried with sodium sulfate. The resulting crude product is purified by chromatography on silica gel. 5.2 g (17.2 mmol) of 4-chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]propyl}-1H-pyrazole are obtained.

The spectroscopic data for the identification of this product are presented in Table II.

PROCEDURE E Example 2a. Preparation of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole.

A solution of 13.4 g (38.2 mmol) of 1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-benzimidazole, 150 ml of concentrated HCl and 75 ml of ethanol is heated at reflux for 6 hours. the ethanol is evaporated, the aqueous solution is cooled, basified with dilute NaOH and extracted with chloroform. The organic phase is dried with anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which is purified by chromatography on silica gel. 9.1 g (27.5 mmol) of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole are obtained.

The melting point and spectroscopic properties for identification of this product are given in Table II.

PROCEDURE F Example 11. Preparation of 4,5-dichloro-1-{4-[hydroxy-4-(4-methylphenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole.

To a suspension of 1.08 g (11.4 mmol) of MgCl2 in 15 ml of anhydrous tetrahydrofuran at -40°C and under a nitrogen atmosphere is added a solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-{4-[4-oxo-1-piperidinyl]butyl}-1H-imidazole in 10 ml of anhydrous THF. The mixture is stirred for 5 minutes, then 6.8 ml of a solution of 1.0 M 4-methylphenylmagnesium bromide is added at -40°C. The resulting suspension is stirred for 15 minutes at -40°C and for 3 hours at ambient temperature. Then an aqueous ammonium chloride solution is added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude product which is purified by chromatography on silica gel to give 1.02 g (2.6 mmol) of 4,5- dichloro 1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole.

The spectroscopic data for the identification of this product can be found in Table I.

PROCEDURE G Example 16a. Preparation of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole.

To a solution of 3.3 g (10 mmol) of 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]-3-oxobutyl}- 1H-pyrazole in 25 ml of THF is added 2.0 g of LiAlH₄. The resulting mixture is allowed to reflux for 2 hours. The excess of LiAlH₄ is destroyed by adding concentrated NaOH and water. The inorganic salts are filtered off and the THF is evaporated in vacuo to give 2.6 g (8.2 mol) of 1-{4-(4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole.

The melting point and spectroscopic data for identification of this product are given in Table II.

PROCEDURE H Example 11a. Preparation of the hydrochloride of 4,5-dichloro-2-methyl-1-{4-[4-phenyl-1-(1,2,3,6- tetrahydropyridinyl)]butyl}-1H-imidazole

To a solution of 7.4 g (20.3 mmol) of 4,5-dichloro-2-methyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole in 15 ml of absolute ethanol, cooled in an ice bath, are added 2.5 ml of an 8.4 N ethanolic hydrochloric acid solution. After a few minutes a precipitate appears which is filtered off, washed with cold ethanol and dried to give 7.7 g (19.2 mmol) of 4,5-dichloro-2-methyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride.

The melting point and spectroscopic data for identification of this product are given in Table II. TABLE I TABLE I (cont.) TABLE I (cont.) TABLE I (cont.) TABLE I (cont.) TABLE I (cont.) TABLE I (cont.) TABLE II TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.) TABLE II (cont.)

BIOLOGICAL TESTS BINDING TO THE (5HT1A) SEROTONIN RECEPTOR

A rat hippocampal homogenate is used following a modification of the method of S. J. Peroutka, J. of Neurochem., 47(2), 529-540 (1986). [3H]8-OH-DPAT is used as the radioligand and serotonin is used to measure non-specific binding. The incubation time is 15 minutes at a temperature of 37ºC. The radioligand bound to the protein is separated by filtration through glass fiber filters and the radioactivity retained on the filter is determined by liquid scintillation. The inhibition constants (Ki, nM) are calculated by non-linear regression analysis using the program EBDA/LIGAND (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)).

BINDING TO THE SIGMA RECEPTOR

Guinea pig brain homogenate (excluding the cerebellum) is used, following a modification of the method of L. Radesca et al., J. Med. Chem., 34, 3058-3065 (1991). [3H](+)-3-PPP is used as the radioligand and haloperidol is used to measure non-specific binding. The incubation time is 120 minutes at a temperature of 25ºC. The radioligand bound to the protein is separated by filtration through glass fiber filters and the radioactivity retained on the filter is determined by liquid scintillation. The inhibition constants (Ki, nM) are calculated by non-linear regression analysis using the EBDA/LIGAND program (Munson and Rodbard, Analytical Biochemistry, 107, 220 (1980)). TABLE III BINDING

The daily dose in human medicine is between 1 milligram and 500 milligrams of substance, which can be administered in one or more doses. Compositions are prepared in the form of formulations compatible with the mode of administration used, for example tablets, dragees, capsules, suppositories, solutions or suspensions. These compositions are prepared by known methods and comprise 1 to 60% by weight of the active ingredient (compound of general formula (I)) and 40 to 99% by weight of a suitable pharmaceutical vehicle compatible with the active ingredient and the physical form of the composition used. The formula of a tablet containing a substance of the invention is given as an example.

Example of a formula for a tablet

Example 11a 5 mg

Lactose 60 mg

Crystalline cellulose 25 mg

Povidone K 90 5 mg

Pregelatinized starch 3 mg

Colloidal silicon dioxide 1 mg

Magnesium stearate 1 mg

Total weight 100 mg

Claims (79)

1. Compounds of the general formula (1) and their physiologically acceptable salts, in the R₁, R₂ and R₃, identical or different, each represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical comprising 1 to 6 carbon atoms, a perfluoroalkyl radical, a phenyl radical optionally substituted by a halogen or a linear or branched alkyl radical comprising 1 to 6 carbon atoms, or an alkoxy radical, it being possible for two adjacent radicals to form an aromatic or saturated cycle; A represents a carbon atom and the dashed line represents an additional bond; n stands for 4; Z₁ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₄ ; Z₂ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₅ ; Z₄ represents a nitrogen atom or a substituted carbon atom which may be represented by C-R₇ ; R₄, R₅, R₆ and R₇, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical comprising 1 to 6 carbon atoms, a hydroxyl radical, an alkoxy radical, a phenyl radical optionally substituted by a halogen or a linear or branched alkyl radical comprising 1 to 6 carbon atoms, or two adjacent radicals can be part of another cycle, aromatic or not, where the group does not contain a carbonyl function and does not represent a tricyclic residue. 2. Compounds included in the general formula (1) according to claim 1 and selected from the following group: 1. 4-Chloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole 2. 4,5-Dichloro-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2-methyl-1H-imidazole 3. 1-[4-(4-Hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-benzimidazole 4. 1-[4-Hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-1,2,4-triazole 5. 4-Chloro-1-{4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-pyrazole 6. 4,5-Dichloro-1-{4-[4-hydroxy-4-(4-chlorophenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole 7. 4-Chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole 8. 4,5-Dichloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole 9. 4,5-Dichloro-1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2-methyl-1H-imidazole 10. 1-[4-(4-Hydroxy-4-phenyl-1-piperidinyl)butyl}indole 11. 4,5-Dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]butyl}-2-methyl-1H-imidazole 12. 1-[4-(4-Hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole 13. 1-[4-(4-Hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-indazole 14. 2-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-2-H-indazole 15. 4-Chloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]butyl}-1H-pyrazole 16. 4-Chloro-1-{4-[4-hydroxy-4-(4-methoxyphenyl)-1-piperidinyl]butyl}-pyrazole 17. 1-[4-(4-Hydroxy-4-phenyl-1-piperidinyl)butyl]-2-phenyl-1H-imidazole 18. 1-{4-[4-Hydroxy-4-(4-methylphenyl)-1-piperidinyl]butyl}-1H-benzimidazole 19. 4,5-Diphenyl-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-imidazole 20. 4-Chloro-1-{4-[4-hydroxy-4-(1-naphthyl)-1-piperidinyl]butyl}-1H-pyrazole 21. 4-Chloro-1-{4-[4-hydroxy-4-(2-naphthyl)-1-piperidinyl]butyl}-1H-pyrazole 22. 4-Chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 23. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole 24. 1-{4-[4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl)butyl}-1H-1,2,4-triazole 25. 4-Chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 26. 4,5-Dichlor 1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole 27. 4-Chloro-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 28. 4,5-Dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole 29. 4-Chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 30. 4,5-Dichloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole 30. 4,5-Dichloro-1-{4-[4-(4-fluorophenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole 32. 4,5-Dichloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole hydrochloride 33. 4,5-Dichloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole hydrochloride 34. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}indole 35. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}indole 36. 4,5-Dichloro-2-methyl-1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]bulyl}-1H-imidazole 37. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 38. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole 39. 2-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-indazole 40. 4-Chloro-1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 41. 4-Chloro-1-{4-[4-(4-methoxyphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 42. 2-Phenyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole 43. 1-{4-[4-(4-methylphenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole 44. R₄, R₅, R₆ and R₇ are not part of another cycle, aromatic or not, 4,5-diphenyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole 45. 4-Chloro-1-{4-[4-(1-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 46. 4-Chloro-1-{4-[4-(2-naphthyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole 47. 1-{4-[4-Phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride 48. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole 49. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzimidazole hydrochloride 50. 4,5-Dichloro-2-methyl-1-{4-[4-(3-trifluoromethylphenyl)]-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride 51. 4-Chloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyropyrinyl)]butyl}-1H-pyrazole hydrochloride 52. 1-{4-[4-(4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole hydrochloride 53. 4,5-Dichloro-1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-imidazole hydrochloride 54. 4-(4-Chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride, 55. 4-(4-Chlorophenyl)-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butylbutyl}-pyrazole 56. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride 57. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole 58. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2-methyl-1H-benzimidazole 59. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole 60. 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-indazole 61. 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole hydrochloride 62. 2-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-2H-benzotriazole 63. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole hydrochloride 64. 1-{4-[4-(4-fluorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-benzotriazole 65. 4-Chloro-1-{4-[4-(4-chlorophenyl)-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride 66. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrazole hydrochloride 67. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-triazole hydrochloride 68. 2-Phenyl-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-imidazole hydrochloride 69. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole hydrochloride 70. 1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-pyrrole 71. 4-(4-Chlorophenyl)-1-[4-(4-hydroxy-4-phenyl-1-piperidinyl)butyl]-1H-pyrazole 72. 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-benzimidazole 73. 4-Chloro-1-{4-[4-hydroxy-4-(3-trifluoromethylphenyl)-1-piperidinyl]butyl}-1H-pyrazole 74. 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-1H-indazole 75. 2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-indazole 76. 2-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-benzotriazole 77. 1-{4-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]butyl}-2H-benzotriazole 78. 3-Chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole 79. 3-Chloro-1-{4-[4-phenyl-1-(1,2,3,6-tetrahydropyridinyl)]butyl}-1H-indazole hydrochloride. 3. Process for the preparation of compounds of the general formula (I) according to one of claims 1 or 2, characterized in that at least one of the following reactions is carried out: 3.1. Conversion of a spirane compound of general formula (II) in the R₁, R₂, R₃ and A have the meaning given above, m is 3 and X is a leaving group such as chlorine, bromine, mesyloxy or tosyloxy, with a nitrogen heterocycle of the general formula (III) in the Z₁, Z₂, Z₄ and R₆ have the meaning given above; 3.2. simultaneous "one-pot" reaction between a derivative of the general formula (IV), an alkylating agent of the general formula (V) and a nitrogen heterocycle of the general formula (III) wherein R₁, R₂, R₃, A, X, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above, 3.3. Conversion of amines of the general formula (IV) in the R₁, R₂, R₃ and A have the meaning given above, with derivatives of the general formula (VI), in the X, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above, under alkylation conditions. 3.4 Conversion of a compound of general formula (VII) in the R₁, R₂, R₃, n, X and A have the meaning given above, with a nitrogen heterocycle of the general formula (III) in the Z₁, Z₂, Z₄ and R₆ have the meaning given above, under alkylation conditions; 3.5 Dehydration of compounds of general formula (I) in the R₁, R₂, R₃, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above, A represents a carbon atom united to a hydroxyl group (C-OH) and the dashed line represents the absence of an additional bond; 3.6 Addition of organometallic reagents - for example phenyllithium or phenylmagnesium bromide - to compounds of the general formula (VIII) in the n, Z₁, Z₂, Z₄ and R₆ have the meaning given above; 3.7 Reduction of compounds of general formula (IX) in the R₁, R₂, R₃, A, n, Z₁, Z₂, Z₄ and R₆ have the meaning given above. 4. Compounds of general formula (I) and their physiologically acceptable salts according to one of claims 1 or 2 as medicaments, in particular as medicaments with a therapeutic effect in the treatment of anxiety, psychosis, epilepsy, convulsions, motor problems, amnesia, cerebrovascular diseases, senile dementia. 5. Pharmaceutical compositions, characterized by the fact that they contain, in addition to a pharmaceutically acceptable carrier, at least one compound of general formula (I) or one of its physiologically acceptable salts according to one of claims 1 or 2.